6‐Aryl and Heterocycle Quinazoline Derivatives as Potent EGFR Inhibitors with Improved Activity toward Gefitinib‐Sensitive and ‐Resistant Tumor Cell Lines. Issue 9 (11th July 2013)

• Record Type: Journal Article
• Authors: Hamed, Mostafa M.; Abou El Ella, Dalal A.; Keeton, Adam B.; Piazza, Gary A.; Abadi, Ashraf H.; Hartmann, Rolf W.; Engel, Matthias
• Is Part Of: ChemMedChem. Volume 8:Issue 9(2013:Sep.)
• Page Start: 1495
• Page End: 1504
• Publication Date: 2013-07-11
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201300147
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>A group of novel anilinoquinazoline derivatives with variable aryl and heterocyclic substituents at position 6 were synthesized and tested for their EGFR‐inhibitory activity. Aryl and heterocyclic rings were attached to the quinazoline scaffold through different linkages such as imine, amide, and thiourea. Most of the aryl and heterocyclic derivatives showed potent inhibition of wild‐type EGFR with IC₅₀ values in the low nanomolar range. Among these, thiourea derivatives <bold>6 a</bold>, <bold>6 b</bold> and compound <bold>10 b</bold> also retained significant activity toward the gefitinib‐insensitive EGFR^T790M/L858R mutant, displaying up to 24‐fold greater potency than gefitinib. In addition, cell growth inhibitory activity was tested against cancer cell lines with wild‐type (KB cells) and mutant EGFR (H1975 cells). Several compounds including <bold>6 a</bold> were found to be more potent than the reference compound gefitinib toward both cell lines, as was the case for compound <bold>10 b</bold> against H1975 cells. Therefore, compounds <bold>6 a</bold> and <bold>10 b</bold> in particular may serve as new leads for the development of inhibitors effective against wild‐type EGFR as well as gefitinib‐resistant mutants.</p> </abstract>